Reduction of the 3-oxo group

A 3a-hydroxysteroid dehydrogenase active on 7a-hydroxy-5 -cholestan-3-one and 7a,12a-dihydroxy-5 -cholestan-3-one (cf. Fig. 3), was partially purified (about 300-fold) from rat Uver cytosol by Berseus [112,113]. NADPH was required as cofactor and hardly any activity was observed with NADH. The preparation was also active towards 3-oxo steroids of the Cjg, C21 and C24 series, and in these cases appreciable activity was obtained also with NADH. The mechanism of reduction involves a stereospecific transfer of a hydride ion from the 4A position of NADPH to the 3)S position of the steroid [114], 

26-Hydroxylation (cf. Fig. 4) is catalysed both by the microsomal and the mitochondrial fraction of a rat liver homogenate [39,40]. In a human liver homogenate, however, there is only very small or insignificant 26-hydroxylation in the microsomal fraction [41]. Both the microsomal and the mitochondrial hydroxylation will be discussed here. 

26-Hydroxylation corresponds to hydroxylation of one of the two terminal methyl groups in the steroid side chain. Since such a substitution creates an asymmetric 

That the mitochondrial system almost exclusively hydroxylates the 25-pro-5 methyl group was later confirmed in vitro with 5)8-cholestane-3a,7a,12a-triol and 5/8-cholestane-3 ,7a-diol as substrates [123,124]. Gustafsson and Sjostedt showed that the microsomal fraction of rat liver mainly hydroxylates the 25-pro-/ methyl group of 5)S-cholestane-3a,7 ,12a-triol [125]. 

In accordance with this, Shefer et al. found that the 255 isomer of 5)8-cholestane-3a,7a-26-triol was the major product after incubation of 5)S-cholestane-3a,7a-diol with the microsomal fraction of liver from several species [124]. 

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Ethynodiol diacetate (53) is prepared by reduction of the 3-oxo group of norethindrone (28) with lithium tributoxyalurninum hydride, followed by acylation with acetic anhydride-pyridine (78,79). It has been reported that higher yields can be obtained in the reduction step by using triethylanainoalurninum hydride (80). 

Amino-2-methoxyphenyl)perhydropyrido[l,2-tf]pyrazine was prepared from a 2-(5-nitro-2-methoxyphenyl)-3-one derivative by catalytic hydrogenation over Pd/C catalyst, followed by the reduction of the 3-oxo group by treatment with BH3-THF complex <1999WO99/042465>. A nitro group was reduced to an amino group in 2-[4-(3-nitrophenyl)piperazin-l-yl]butyl]perhydropyrido[l,2-tf]pyrazine-l,4-dione <2001JME186>, in 8-hydroxy-... 

The 7/ -fluoro-substituent in the e-homo-oestrane derivatives (69) is unusually stable, surviving aromatization of ring a, or reduction of the 3-oxo-group by lithium aluminium hydride, except in refluxing diglyme. ... 

The passage to cortisone (334) began with the three-stage conversion of the ester (325) into the -monodehydro derivative (329). Conversion of the latter into the 3,11-diketo compound (330) was effected via the 90, 110 -oxide [1005-1007]. Reduction of the 3-oxo group and acetylation... 

Lynestrenol is the des-3-oxo derivative of norethindrone (28). It has been prepared through a similar synthetic pathway as aHylestrenol (37) (52), ie, addition of potassium acetyUde, rather than aHyl magnesium bromide, affords lynestrenol (73). Lynestrenol is also available from norethindrone (28). Reduction of the 3-keto group is accompHshed by treating norethindrone (28) with sodium borohydride in the presence of trifluoro- or trichloroacetic acid... 

Selective reduction of the 7-oxo group in pyrido[23-synthetic approach to 5,10-dideazatetrahydrofolic acid <00H(53)1207>. Cycloaddition of pyrimido[4,5-c][l,2,5]oxadiazine 96 with 2,3-dihydrofuran affords a new synthesis of dimethyllumazine derivative 97 which undergoes a ring-opening reaction to give pyrazine derivative 98 <00JHC419>. 

Cyclic sulphites have been prepared from 3a,5-dihydroxy-5a-cholestan-6-one and its 3/),5/l-isomer. ° The compounds exist with the six-membered sulphite ring in a boat conformation. Reduction of the 6-oxo-group in the 3 6,5)8-compound... 

Reduction of Ketones.—Selective reduction of the 20-oxo-group in 17a,21-dihydroxy-pregn-4-ene-3,20-dione (Reichstein s S) with sodium borohydride in methanol at 0 °C gave the 20fi- and 20a-ols in ratio 2 1, contrary to an earlier report that the 20jS-ol is formed almost exclusively. 

A study of the reduction of [24- C]3-oxo-5j8-cholanic acid in bile fistula rats given [l- Hjjethanol showed that all metabolites had a 3a-hydroxy group and all radioactive products (lithocholate, 3a,6/8-dihydroxy-5 -cholanate, chenodeoxycho-late and y8-muricholate) contained about 13 atom% excess deuterium in the 3/9 position. Thus, the 3)8-hydroxy-5/9-steroid dehydrogenase isoenzyme of alcohol dehydrogenase [172] has no function in the reductive metabolism of bile acids. Cholic acid was not radioactive but contained deuterium at the 3)8, 5)8 and other positions, probably because of the transfer of deuterium from ethanol via NADH to NADPH, which it utilized in the biosynthesis of cholesterol and bile acids and in oxido reduction of the 3-hydroxyl group of the latter [173]. 

The in situ catalyst [Rh(cod)Cl],/Cp-ProNOP (see Section 2.3.1.2.2.). especially successful in the hydrogenation of 4,4-dimethyloxolane-2,3-dione, was applied to the reduction of the 2-oxo group in rV-benzyl-2-oxo-2-phenylacetamide19. (S)-jY-Benzyl-2-hydroxy-2-phenylacetamide was obtained in 79% ee (Table 4). The substrate/catalyst ratio could be increased to 1000 1. The 4-hydroxy derivative of iV-benzyl-2-oxo-2-phenylacetamide gave (5)-jV-benzyl-2-hydroxy-2-(4-hydroxyphenyl)acetamide in 66% ee19. 

A conjugated 3-oxo group is not easily reduced by yeast however. Clostridium paraputrificum selectively reduces these steroids to the 3a-hydroxy compounds. Reduction of the 17-oxo group to 17/ -hydroxysteroids can be achieved with baker s yeast, while reduction of the 20-oxo group can be performed in most cases with S treptomyces strains. 

D-homoestrone have been synthesized from the ketone (559) [442, 614]. Subsequent reduction, hydrolysis, and oxidation have enabled (559) to be converted into the triketone (560), which cyclizes into the da, lOp -ketol (562) during chromatography on Florex. Dehydration and reduction of the 17a-oxo group lead to the 3-oxo-A > derivative (563). Isomerization of the latter into D-homoestradiol (564) takes place in low yield when it is boiled with palladized carbon. 

In the absence of the 11-oxo-group the main product is the 2,3-dioxo-compound. The structure of the major product arising from autoxidation and (EtO)3P reduction of the enol (116) has been confirmed as the 17a-hydroxy-compound (117) by an X-ray analysis, and the minor product of this reaction sequence was thereby shown to be the n-epimer. " ... 

Chlorotrimethylsilane with zinc in THF reduces 3-oxo-5 a-steroids directly to A2-olefinic derivatives, but most other oxo-groups are unreactive, allowing selective attack on the 3-oxo-group in diones.178 The 5)8-steroidal iminium perchlorate (204), obtained179 by reduction of the A4-unsaturated analogue with the Hantzsch ester (a dihydropyridine), can be reduced further with the same reagent to give the 3/3-pyrrolidinium salt (205) stereospecifically.180... 

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